Evaluation of the risk of venous thromboembolism in patients with bullous pemphigoid: a single-centre retrospective cohort study

Abstract

Objective: Bullous pemphigoid (BP) is an autoimmune blistering disease that predominantly affects elderly individuals. It has been associated with various comorbidities, including neuropsychiatric disorders and diabetes mellitus. In patients with BP, elevated levels of prothrombin and D-dimer, as well as increased tissue factor expression, have been frequently observed, which may lead to endothelial activation. Its pathophysiology and predilection for older age may contribute to an increased risk of venous thromboembolism (VTE). Therefore, in this study, we aimed to retrospectively investigate the clinical characteristics, survival, frequency of VTE, and its impact on survival in patients diagnosed with BP. Methods: In this study, the clinical characteristics, survival duration, VTE incidence, and its impact on survival were retrospectively evaluated in patients who presented to Zonguldak Bülent Ecevit University between 2010-2024 and had a clinical and histopathological diagnosis of BP. Results: A total of 53 patients (37 female, 16 male) were included in the study. The mean age at diagnosis was 75.15 years (± 9.7). The most common comorbidities were diabetes mellitus (n=35) and hypertension (n=30). The median survival time was estimated at 39 months according to survival analysis. VTE was observed in 3 patients (5.7%). The incidence rate of VTE in BP patients was 42.6 per 1,000 person-years. The incidence rate of VTE in BP was found to be statistically significantly higher compared with the incidence rate of VTE in the population over 18 years of age and in the elderly population in population-based studies (p<0.001 and p<0.001). Thromboembolic events developed within one year following the diagnosis of BP. According to the survival analysis, VTE did not affect mortality (p=0.978). Conclusion: In our study, an increased incidence of VTE was demonstrated in patients diagnosed with BP. However no significant effect on survival was observed. The increase is attributed to the prothrombotic state induced by inflammatory pathways and comorbidities. We believe that this elevated risk, particularly in the acute phase, is an important factor affecting prognosis that should be considered by clinicians in patient follow-up

Keywords

• bullous pemphigoid
• venous thromboembolism
• survival

Büllöz pemfigoid hastalarında venöz tromboemboli riskinin değerlendirilmesi: tek merkezli retrospektif kohort çalışma

Abstract

Amaç: Büllöz pemfigoid (BP), genellikle yaşlı bireylerde görülen otoimmün büllöz bir hastalıktır. Nöropsikiyatrik hastalıklar, diyabetes mellitus gibi birçok hastalık ile ilişkilendirilmektedir. BP hastalarında sıklıkla endotel aktivasyonuna yol açabilecek artmış protrombin ve D-dimer yüksekliği ile artmış doku faktörü ekspresyonunun olduğu gösterilmiştir. Patofizyolojisi ve ileri yaşta görülmesi venöz tromboemboli (VTE) riskini arttırabilmektedir. Bu nedenle çalışmamızda BP tanısı almış hastaların klinik özelliklerini, sağkalım sürelerini, VTE sıklığını ve bunun sağkalıma etkisini retrospektif olarak incelemeyi planladık. Yöntemler: Bu çalışmada Zonguldak Bülent Ecevit Üniversitesi’ne 2010-2024 yılları arasında başvurmuş klinik ve histopatolojik olarak BP tanısı almış hastaların klinik özellikleri, sağkalım süreleri, VTE sıklığı ve bunun sağkalıma etkisi retrospektif olarak değerlendirildi. Bulgular: Çalışmaya 53 (37 kadın, 16 erkek) hasta dahil edildi. Tanı anında yaş ortalaması 75.15’di(± 9.7). En sık eşlik eden hastalıklar diyabetes mellitus (n=35) ve hipertansiyondu (n=30). Yapılan yaşam analizi sonucunda medyan yaşam süresi 39 ay olarak hesaplandı. VTE, 3 hastada (%5.7) gözlendi. BP hastalarında VTE görülme insidans oranı 1,000 kişi-yıl başına 42.6 olarak hesaplandı. Bu çalışmadaki BP’de VTE insidansı, toplum bazlı çalışmalardaki VTE’nin 18 yaş üzerinde ve yaşlı popülasyonda görülme sıklığı ile karşılaştırıldığında, istatiksel olarak anlamlı derece yüksek bulundu (p<0.001 ve p<0.001). Tromboembolik olay gelişimi BP tanısından sonraki bir yıl içinde gözlendi. Yaşam analizi sonucuna göre, VTE’nin mortalite üzerine etkisi bulunmadı (p=0.978). Sonuç: Çalışmamızda BP tanılı hastalarda VTE insidansının arttığı gösterilmiştir. Ancak sağkalım üzerine anlamlı etkisi gösterilememiştir. Artış, inflamatuar yolakların tetiklediği protrombotik durum ve komorbiditelere bağlanmaktadır. Özellikle akut dönemde artmış bu riskin klinisyenler için hasta takibinde dikkate alınması gereken, prognozu etkileyen önemli bir unsur olduğunu düşünmekteyiz.

Keywords

• büllöz pemfigoid
• venöz tromboembolizm
• yaşam analizi.

References

1. 1.Miyamoto D, Santi CG, Aoki V, Maruta CW. Bullouspemphigoid. An Bras Dermatol. 2019;94:133-46.
2. 2.Kilic Sayar S, Sun GP, Kucukoglu R. Comorbiditiesof bullous pemphigoid: A single-center retrospective case-control study from Turkey. Dermatol Ther.2021;34:e15031.
3. 3.Martin E, Mauer I, Malzahn U, et al. Comorbiddiseases among bullous pemphigoid patients inGermany: new insights from a case-control study. JDtsch Dermatol Ges. 2022;20:798-805.
4. 4.Huttelmaier J, Benoit S, Goebeler M. Comorbidityin bullous pemphigoid: up-date and clinicalimplications. Front Immunol. 2023;14:1196999.
5. 5.Brown LF, Harrist TJ, Yeo KT, et al. Increasedexpression of vascular permeability factor (vascularendothelial growth factor) in bullous pemphigoid,dermatitis herpetiformis, and erythema multiforme.J Invest Dermatol. 1995;104:744-9.
6. 6.Khan F, Tritschler T, Kahn SR, Rodger MA. Venousthromboembolism. Lancet. 2021;398:64-77.
7. 7.Cugno M, Tedeschi A, Borghi A, et al. Activation ofBlood Coagulation in Two Prototypic AutoimmuneSkin Diseases: A Possible Link with Thrombotic Risk. PLoS One. 2015;10:e0129456.
8. 8.Cugno M, Marzano AV, Bucciarelli P, et al.Increased risk of venous thromboembolism inpatients with bullous pemphigoid. The INVENTEP(INcidence of VENous ThromboEmbolism in bullousPemphigoid) study. Thromb Haemost.2016;115:193-9.

9. 9.Ungprasert P, Wijarnpreecha K, Thongprayoon C.Risk of venous thromboembolism in patients withbullous pemphigoid: A systematic review and meta-analysis. Indian J Dermatol Venereol Leprol.2018;84:22-6.
10. 10.Chen CL, Wu CY, Lyu YS, et al. Associationbetween bullous pemphigoid and risk of venousthromboembolism: A nationwide population-basedcohort study. J Dermatol. 2022;49:753-61.
11. 11.Wendelboe AM, Campbell J, Ding K, et al.Incidence of Venous Thromboembolism in a Racially Diverse Population of Oklahoma County, Oklahoma.Thromb Haemost. 2021;121:816-25.
12. 12.Kimball AS, Obi AT, Diaz JA, Henke PK. TheEmerging Role of NETs in Venous Thrombosis andImmunothrombosis. Front Immunol. 2016;7:236.
13. 13.Fang H, Shao S, Xue K, et al. Neutrophilextracellular traps contribute to immunedysregulation in bullous pemphigoid via inducing B-cell differentiation and antibody production. FASEBJ.2021;35:e21746.
14. 14.Jones VA, Patel PM, Amber KT. Eosinophils inbullous pemphigoid. Panminerva Med.2021;63:368-78.
15. 15.Limberg MM, Weihrauch T, Gray N, et al.Eosinophils, Basophils, and Neutrophils in BullousPemphigoid. Biomolecules. 2023;13.
16. 16.Marzano AV, Tedeschi A, Berti E, et al. Activationof coagulation in bullous pemphigoid and othereosinophil-related inflammatory skin diseases. ClinExp Immunol. 2011;165:44-50.
17. 17.Ramirez GA, Yacoub MR, Ripa M, et al.Eosinophils from Physiology to Disease: AComprehensive Review. Biomed Res Int.2018;2018:9095275.
18. 18.Xu WJ, Wang S, Yuan P, et al. Arterial and venousthromboembolism risk associated with bloodeosinophils: A systematic review and meta-analysis.Animal Model Exp Med. 2022;5:470-81.
19. 19.Lippi G, Favaloro EJ. Allergy and VenousThromboembolism: A Casual or CausativeAssociation. Semin Thromb Hemost. 2016;42:63-8.
20. 20.Johannesdottir SA, Horvath-Puho E, Dekkers OM,et al. Use of glucocorticoids and risk of venousthromboembolism: a nationwide population-basedcase-control study. JAMA Intern Med.2013;173:743-52.